Increased pulmonary arteriolar tone associated with lung oxidative stress and nitric oxide in a mouse model of Alzheimer's disease.

Vascular dysfunction and decreased cerebral blood flow are linked to Alzheimer's disease (AD). Loss of endothelial nitric oxide (NO) and oxidative stress in human cerebrovascular endothelium increase expression of amyloid precursor protein (APP) and enhance production of the Aβ peptide, suggesting that loss of endothelial NO contributes to AD pathology. We hypothesize that decreased systemic NO bioavailability in AD may also impact lung microcirculation and induce pulmonary endothelial dysfunction.

The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer's disease.

Background: The pathological features of the common neurodegenerative conditions, Alzheimer's disease (AD), Parkinson's disease and multiple sclerosis are all known to be associated with iron dysregulation in regions of the brain where the specific pathology is most highly expressed. Iron accumulates in cortical plaques and neurofibrillary tangles in AD where it participates in redox cycling and causes oxidative damage to neurons. To understand these abnormalities in the distribution of iron the expression of proteins that maintain systemic iron balance was investigated in human AD brains and in the APP-transgenic (APP-tg) mouse.

Cross-kingdom sequence similarities between human micro-RNAs and plant viruses.

Micro-RNAs regulate the expression of cellular and tissue phenotypes at a post-transcriptional level through a complex process involving complementary interactions between micro-RNAs and messenger-RNAs. Similar nucleotide interactions have been shown to occur as cross-kingdom events; for example, between plant viruses and plant micro-RNAs and also between animal viruses and animal micro-RNAs. In this study, this view is expanded to look for cross-kingdom similarities between plant virus and human micro-RNA sequences.

Aquaporin 4 molecular mimicry and implications for neuromyelitis optica.

Neuromyelitis optica (NMO) is associated with antibodies to aquaporin 4 (AQP4). We hypothesized that antibodies to AQP4 can be triggered by exposure to environmental proteins. We compared human AQP4 to plant and bacterial proteins to investigate the occurrence of significantly similar structures and sequences.

Humans have antibodies against a plant virus: evidence from tobacco mosaic virus.

Tobacco mosaic virus (TMV), a widespread plant pathogen, is found in tobacco (including cigarettes and smokeless tobacco) as well as in many other plants. Plant viruses do not replicate or cause infection in humans or other mammals. This study was done to determine whether exposure to tobacco products induces an immune response to TMV in humans.

Lipid peroxidation-derived reactive aldehydes directly and differentially impair spinal cord and brain mitochondrial function.

Mitochondrial bioenergetic dysfunction in traumatic spinal cord and brain injury is associated with post-traumatic free radical-mediated oxidative damage to proteins and lipids. Lipid peroxidation by-products, such as 4-hydroxy-2-nonenal and acrolein, can form adducts with proteins and exacerbate the effects of direct free radical-induced protein oxidation. The aim of the present investigation was to determine and compare the direct contribution of 4-hydroxy-2-nonenal and acrolein to spinal cord and brain mitochondrial dysfunction.

Antioxidant therapies for traumatic brain injury.

Free radical-induced oxidative damage reactions, and membrane lipid peroxidation (LP), in particular, are among the best validated secondary injury mechanisms in preclinical traumatic brain injury (TBI) models. In addition to the disruption of the membrane phospholipid architecture, LP results in the formation of cytotoxic aldehyde-containing products that bind to cellular proteins and impair their normal functions. This article reviews the progress of the past three decades in regard to the preclinical discovery and attempted clinical development of antioxidant drugs designed to inhibit free radical-induced LP and its neurotoxic consequences via different mechanisms including the O(2)(*-) scavenger superoxide dismutase and the lipid peroxidation inhibitor tirilazad.

Cellular and molecular characterization of oxidative stress in olfactory epithelium of Harlequin mutant mouse.

Oxidative stress in the olfactory system is a major factor associated with age-related olfactory impairment, although the mechanisms by which this occurs are not completely understood. The Harlequin mutant mouse (Hq/Y), which carries an X-linked recessive mutation in the Aifm1 gene, is a model of progressive oxidative stress-induced neurodegeneration in the cerebellum and retina. To determine whether the Hq/Y mutant mouse is a suitable model of oxidative stress-associated olfactory aging, we investigated cellular and molecular changes in the olfactory epithelium (OE) and olfactory bulb (OB) of 6-month-old male Hq/Y mice compared to those in sex-matched littermate controls (+/Y) and in age- and sex-matched C57BL/6 mice.

Oxidative stress in the aging murine olfactory bulb: redox proteomics and cellular localization.

A recent proteomics analysis from our laboratory demonstrated that several oxidative stress response proteins showed significant changes in steady-state levels in olfactory bulbs (OBs) of 20- vs. 1.5-month-old mice.

Proteomic identification of differentially expressed proteins in the aging murine olfactory system and transcriptional analysis of the associated genes.

Decline in olfactory ability has been associated with aging as well as neurodegenerative disorders. The aim of this study was to gain fundamental insight into molecular events associated with the aging olfactory system. We report a comparative proteomic analysis of the olfactory epithelium (OE) and olfactory bulb (OB) of old (80-week old) and young (6-week old) mice with further analysis of age-related differences in differentially expressed proteins at the mRNA level using real-time RT-PCR.

Quantitative proteomics analysis of differential protein expression and oxidative modification of specific proteins in the brains of old mice.

The brain is susceptible to oxidative stress, which is associated with age-related brain dysfunction, because of its high content of peroxidizable unsaturated fatty acids, high oxygen consumption per unit weight, high content of key components for oxidative damage, and the relative scarcity of antioxidant defense systems. Protein oxidation, which results in functional disruption, is not random but appears to be associated with increased oxidation in specific proteins. By using a proteomics approach, we have compared the protein levels and specific protein carbonyl levels, an index of oxidative damage in the brains of old mice, to these parameters in the brains of young mice and have identified specific proteins that are altered as a function of aging.

Temporal profiling of gene expression during neurogenesis and remodeling in the olfactory epithelium at short intervals after target ablation.

Neurogenesis in the olfactory epithelium (OE) is induced by olfactory bulbectomy (OBX), which effectively axotomizes olfactory sensory neurons (OSNs) and removes their synaptic targets, resulting in apoptosis. We used Affymetrix high-density oligonucleotide arrays to investigate changes in gene expression during initiation of signaling in pathways that regulate apoptosis and neurogenesis in the murine OE at 2, 8, 16, and 48 hr after bilateral OBX compared to that in sham-operated controls. We focused on regulation of a defined set of genes associated with apoptosis, stem/progenitor cell regulation, and cell cycle progression because of the activation of these processes in OE degeneration and remodeling after OBX.

Target ablation-induced regulation of macrophage recruitment into the olfactory epithelium of Mip-1alpha-/- mice and restoration of function by exogenous MIP-1alpha.

The chemokine macrophage inflammatory protein (MIP)-1alpha recruits macrophages to sites of epithelial remodeling. We showed previously that mRNA and protein levels of MIP-1alpha in the olfactory epithelium (OE) increased significantly at 3 days after bilateral olfactory bulbectomy (OBX). The first aim of this study was to investigate the effect of the absence of MIP-1alpha on macrophage recruitment to the OE 3 days after OBX in Mip-1alpha(-/-) mice compared with C57BL/6 mice and to test whether chemokine function could be restored by MIP-1alpha protein injection into Mip-1alpha(-/-) mice.